Preparation of diazabicyclic Intermediates

ABSTRACT

Diazabicyclo[2.2.1]heptane intermediates are prepared from 4-hydroxy-L-proline in a five step procedure, or from allo-4-hydroxy-D-proline, through a novel 2-(C 1  -C 6 )alkyl-5-substituted-2,5-diazabicyclo[2.2.1]heptane intermediate. The diazabicycloheptanes are of use in the preparation of antibiotic quinolones.

This is a continuation of application Ser. No. 07/665,380, filed on Mar.4, 1991, abandoned, which is a division of U.S. Ser. No. 07/423,063,filed Oct. 18, 1989, now U.S. Pat. No. 5,036,153, which is acontinuation-in-part of U.S. Ser. No. 350,423, filed May 11, 1989, nowabandoned.

BACKGROUND OF THE INVENTION

The invention relates to the preparation of2,5-diazabicyclo[2.2.1]heptane intermediates of use in the preparationof antibiotic quinolones such as disclosed in U.S. Pat. No. 4,775,668.

A method for the synthesis of 2,5-diazabicyclo[2.2.1]heptanes isdescribed in Portoghese et al, J. Org. Chem., 31, 1059 (1966). Accordingto this method, hydroxy-L-proline is transformed intotritosylhydroxy-L-prolinol which is first reacted with benzylamine andthen hydrogen iodide, phosphorus, and acetic acid to form2-benzyl-2,5-diazabicyclo[2.2.1]heptane dihydroiodide. U.S. Pat. No.3,947,445 follows a similar procedure and then converts thedihydroiodide through a three step procedure into2-methyl-2,5-diazabicyclo[2.2.1]heptane.

SUMMARY OF THE INVENTION

The invention relates to a process for preparing a2,5-diazabicyclo[2.2.1]heptane derivative of the formula IA ##STR1## orthe enantiomer, racemate, or acid addition salt thereof, wherein Y ishydrogen or XR₂, R₁ is hydrogen or C₁ -C₆ alkyl, and X and R₂ are asdefined below, by (a) reacting a compound of the formula ##STR2## or theenantiomer or the racemate thereof, wherein X is SO₂ or CO₂, R₂ and R₃are each independently C₁ -C₆ alkyl, trifluoromethyl, benzyl, or phenyloptionally substituted by one or two C₁ -C₆ alkyl, halogen, nitro,methoxy or trifluoromethyl, and R₄ is halogen or OSO₂ R₃ wherein R₃ isas defined above, with a (C₁ -C₆) alkylamine or ammonia to form acompound of the formula IA wherein Y is XR₂, and X, R₁ and R₂ are asdefined above, and, if desired, (b) reducing or hydrolyzing the compoundof formula IA wherein Y is XR₂ to form a compound of formula IA whereinY is hydrogen.

In a preferred embodiment of this process, said C₁ -C₆ alkylamine ismethylamine, X is SO₂, and R₂ is p-tolyl.

The invention also relates to a compound of the formula II ##STR3## orthe enantiomer or racemate thereof, wherein X is SO₂ or CO₂, R₂ is C₁-C₆ alkyl, trifluoromethyl, benzyl, or phenyl optionally substituted byone or two C₁ -C₆ alkyl, halogen, nitro, methoxy or trifluoromethyl, andR₅ is C₁ -C₆ alkyl.

Preferably, X is SO₂, and R₂ is paratolyl in formula II, and morepreferably, R₅ is methyl, X is SO₂, and R₂ is paratolyl. The compoundsof formula II have optical centers and therefore occur in two differentstereoisomeric configurations, the S,S-configuration and theR,R-configuration. The present invention includes both stereoisomers ofthe compounds of formula II, and also the racemic mixture thereof. Theformulas herein indicate the particular R or S configuration with thedesignation "R" and "S", respectively.

The invention further relates to a process for preparing a compound ofabove formula III, wherein X is SO₂ or CO₂ and R₂ is as defined above,by reacting a compound of the formula ##STR4## or the enantiomer orracemate thereof, wherein X is SO₂ or CO₂, with a compound of theformula

    R.sub.3 SO.sub.2 X.sup.1                                   V

wherein R₃ is C₁ -C₆ alkyl, trifluoromethyl, or phenyl optionallysubstituted by one or two C₁ -C₆ alkyl, halogen, nitro, methoxy ortrifluoromethyl, and X¹ is halogen or OSO₂ R₃ wherein R₃ is as definedabove. In a preferred embodiment, R₂ is paratolyl and X is SO₂ informula IV.

The invention also relates to a process for preparing a compound ofabove formula IV by reducing a compound of the formula ##STR5## or theenantiomer or racemate thereof, wherein X is SO₂ or CO₂, and R₂ is C₁-C₆ alkyl, trifluoromethyl, or phenyl optionally substituted by one ortwo C₁ -C₆ alkyl, halogen, nitro, methoxy or trifluoromethyl. In apreferred embodiment, the reduction is carried out with sodiumborohydride in the presence of borontrifluoride etherate. In anotherpreferred embodiment, X is SO₂ and R₂ is paratolyl in formula VI.

The invention further relates to a process for preparing a compound offormula VI by reacting 4-hydroxy-L-proline with a compound of theformula

    R.sub.2 X X.sup.1                                          VII

wherein X is SO₂ or CO₂, R₂ is C₁ -C₆ alkyl, trifluoromethyl, benzyl, orphenyl optionally substituted by one or two C₁ -C₆ alkyl, halogen,nitro, methoxy or trifluoromethyl, and X¹ is halogen, an azide or OSO₂R₂, wherein R₂ is as defined above, in the presence of alkali metalcarbonate. In a preferred embodiment, X is SO₂ and R₂ is paratolyl informula VII.

The invention further relates to an alternative process for preparingthe R,R-stereoisomers of the formula IA ##STR6## or an acid additionsalt thereof, wherein R₁ is hydrogen or C₁ -C₆ alkyl, Y is hydrogen orXR₂, X is SO₂ or CO₂, and R₂ is C₁ -C₆ alkyl, trifluoromethyl, benzyl,or phenyl optionally substituted by one or two C₁ -C₆ alkyl, halogen,nitro, methoxy, or trifluoromethyl, by (a) reacting a compound of theformula ##STR7## wherein Y is as defined above, with a C₁ -C₆ alkylamineor ammonia to form a compound of the formula IA wherein Y is XR₂, and X,R₁ and R₂ are as defined above, and, if desired, (b) reducing orhydrolyzing a compound of formula IA wherein Y is XR₂ to form a compoundof formula IA wherein Y is hydrogen. In a preferred embodiment, the C₁-C₆ alkylamine is methylamine and Y is paratolylsulfonyl in step (a).

The invention also relates to a compound of the formula ##STR8## whereinX is SO₂ or CO₂ and R₂ is C₁ -C₆ alkyl, trifluoromethyl, benzyl, orphenyl optionally substituted by one or two C₁ -C₆ alkyl, halogen,nitro, methoxy, or trifluoromethyl. In a preferred embodiment, X is SO₂and R₂ is p-tolyl.

The invention further relates to a process for preparing a compound ofthe formula ##STR9## wherein X is SO₂ or CO₂, and R₂ is C₁ -C₆ alkyl,trifluoromethyl, benzyl, or phenyl optionally substituted by one or twoC₁ -C₆ alkyl, halogen, nitro, methoxy, or trifluoromethyl, by heating acompound of the formula ##STR10## with tosylchloride in pyridine.

DETAILED DESCRIPTION OF THE INVENTION

The term "alkyl" in the definitions of groups R₁, R₂, R₃, R₄ and R₅denotes saturated monovalent straight or branched aliphatic hydrocarbonradicals such as methyl, ethyl, propyl, t-butyl, hexyl, etc. The term"halogen" denotes fluoro, chloro, bromo, or iodo.

Scheme A set out below shows the reaction scheme for the preparation ofthe S,S-stereoisomer of the compound of formula I fromtrans-4-hydroxy-L-proline, including the process steps according to theinvention set out above. The correct stereoisomeric configuration isshown in each one of the formulae by designation of "R" and "S" at theoptical centers in each formula. The R,R-stereoisomer of the compound offormula I may be prepared in a similar manner from the enantiomer of thecompound of formula IV which may be prepared starting fromallo-4-hydroxy-D-proline, described in Baker et al, J. Org. Chem., Vol.46, 2955 (1981).

The formulae given in this Scheme and throughout the present applicationconform to the accepted convention for indicating stereoisomers, namely," " to indicate an atom projecting into the plane of the paper(α-orientation) and " " to indicate an atom projecting out from theplane of the paper (β-orientation) and hence the plane of the moleculeitself.

The above process for preparing a compound of formula I (the compoundsof formula IA wherein Y is hydrogen) by reduction or hydrolysis of acompound of formula II (the compounds of formula IA wherein Y is XR₂) isconveniently carried out by reaction of compound (II) with an aqueous oranhydrous hydrogen halide such as hydrogen chloride, hydrogen iodide andhydrogen bromide, in an acid solvent, such as acetic acid or sulfuricacid. ##STR11## the reaction with hydrogen chloride is a hydrolysis, andthe reaction with hydrogen bromide or hydrogen iodide is a reduction, asdisclosed in Searles et al, Chem. Review, 1077-1103 (1959). The acidsolvent used may be an organic acid such as acetic acid or an inorganicacid such as sulfuric acid. Preferably, the reaction is carried out withaqueous or anhydrous hydrogen bromide in acetic acid. The reaction isgenerally carried out at temperatures of from about room temperature toabout 100° C., preferably at room temperature.

Alternatively, compound (I) may be formed from compound (II) by theelectrochemical reductive cleavage in a mixture of water and an organicsolvent in the presence of an organic electrolyte. Examples of suitableorganic solvents are acetonitrile and acetic acid. An example of asuitable organic electrolyte is a tetra(C₁ -C₆)alkylammonium halide suchas tetraethylammonium bromide. The reaction temperature is usually fromroom temperature to about 50° C.

The above process for producing compound (II) from compound (III) isgenerally conducted with excess alkylamine, preferably at least aboutthree molar equivalents alkylamine. The reaction is usually carried outin a sealed container depending on the alkylamine used. For instance,methylamine and ethylamine are gases at the reaction temperatures andthus require reaction in a sealed container. Generally, the reaction isconducted in an alcoholic solvent or water, preferably methanol orwater. The reaction temperature ranges from about 50° to about 130° C.,and is generally about 90° C.

The process for preparing compound (III) from compound (IV) isconveniently conducted in an inert solvent. Suitable solvents arenon-polar solvents such as toluene and benzene. The reaction isconducted in the presence of a base. Suitable bases are aliphaticorganic bases such as tertiary-(C₁ -C₆)alkyl amine, e.g. triethylamine,or an aromatic organic base such as 2,6-lutidine, pyridine, (C₁-C₆)alkyl-substituted pyridine or N,N-dimethyl-4-aminopyridine.Preferably, the reaction is conducted in pyridine which acts both as abase and a solvent. The compound (V) is present in excess of two molarequivalents, preferably in an amount of about three molar equivalents.The reaction temperature is about 0° to about 50° C., usually about 15°C. (IV) is carried out with a hydride of a metal in Group III of thePeriodic Table, such as lithium aluminum hydride or diborane. Thereduction is carried out in the presence of an ether solvent. Suitablesolvents are di(C₁ -C₆)alkyl ethers, glyme, diglyme and, preferably,tetrahydrofuran. The diborane is preferably generated in situ from thereaction of sodium borohydride with borontrifluoride etherate. Thereduction is conducted at temperatures ranging from about 0° to about45° C., usually about room temperature.

The reaction to form compound (VI) from 4-hydroxy-L-proline and R₂ XX¹is generally conducted in a polar solvent such as water. The reaction isin the presence of an alkali metal carbonate, preferably sodiumcarbonate. The reaction temperature ranges from about 10° to about 50°C., usually about room temperature.

The R,R-stereoisomers of formula II may be prepared fromallo-4-hydroxy-D-proline as set out in Scheme B. The last step in SchemeB is identical to the last step in Scheme A except for thestereochemistry of the compounds of formulae I and II. ##STR12##

The compounds of formula II in Scheme B are prepared by reacting thecompounds of formula IX with a C₁ -C₆ alkylamine or ammonia. The processis generally conducted with excess alkylamine, preferably at least aboutthree molar equivalents alkylamine. The reaction is usually carried outin a sealed container depending on the alkylamine used. For instance,methylamine and ethylamine are gases at the reaction temperatures andthus require reaction in a sealed container. Generally, the reaction isconducted in an alcoholic solvent or water, preferably methanol orwater. The reaction temperature ranges from about 50° to about 130° C.,and is generally about 90° C.

The compounds of formula IX are prepared by reacting compounds of theformula X with tosylchloride in pyridine. The reaction is conducted attemperatures of about 70° to about 115° C., generally at about 90° C.Under these reaction conditions, the R,R-stereoisomers of the formula Xconverts to the R,S-stereoisomer of the compounds of formula IX.

The R,R-stereoisomers of formula X are prepared in identical manner asthe R,S-compounds of formula IV in Scheme A by reduction of theR,R-compounds of formula XI with a hydride in the presence of an ethersolvent, as outlined above.

The R,R-compounds of formula XI are prepared in identical manner as theR,S-stereoisomers of formula VI in Scheme A by reaction ofallo-4-hydroxy-D-proline with R₂ XX¹ in a polar solvent such as water inthe presence of an alkali metal carbonate, preferably sodium carbonate,at a reaction temperature ranging from about 10° to about 50° C.,usually about room temperature.

The following Examples illustrate the invention.

EXAMPLE 1 1-(4-Toluenesulfonyl)-4-hydroxy-L-proline

To a solution of 100 g (763 mmol) of 4-hydroxy-L-proline in 750 ml ofwater was added 169.9 g (1602 mmol) of sodium carbonate at 0° C. alongwith 174.5 g (916 mmol) of 4-toluenesulfonyl chloride (added in 3portions over a period of 1 hour). The slurry was then warmed to roomtemperature and allowed to stir for 48 hours. The reaction was acidifiedwith concentrated hydrogen chloride solution to pH 2 and the product wasisolated via filtration. The filter cake was washed with pH 2 buffer anddried in a vacuum oven at 60° C. for 16 hours to obtain 215.3 g of theproduct as a white crystalline solid in 99% yield. M.P.=149°-151° C.

EXAMPLE 2 (2S,4R)-2-Hydroxymethyl-4-hydroxy-1-(4-toluenesulfonyl)-pyrrolidine

To 2 l of tetrahydrofuran (THF) was added 57.6 g (1523 mmol) of sodiumborohydride and the mixture was cooled to 10° C. before 250 ml (1980mmol) of borontrifluoride etherate was added dropwise over a period of 1hour. Then 215.3 g (755.4 mmol) of1-(4-toluenesulfonyl)-4-hydroxy-L-proline was added carefully in 100 mlof THF and the mixture was allowed to stir for 16 hours. The reactionwas quenched with methanol and 10% aqueous hydrogen chloride solutionwas added and the mixture was gently heated to 60° C. for 1 hour. Thereaction mixture was filtered and the pH was adjusted to neutral with50% aqueous sodium hydroxide solution and the volatiles were evaporatedunder reduced pressure. The product was then isolated via filtration andthe filter cake was washed with water. Drying under vacuum at 60° C. for12 hours yielded 164 g of the product as a white solid in 85 % yield.M.P. 132°-133° C.

EXAMPLE 3 (2S,4R)-1-(4-Toluenesulfonyl)-2-(4-toluenesulfonyloxymethyl)-4-(4-toluenesulfonyloxy)-pyrrolidine

To an ice-cold solution of 170 g (626.5 mmol) of (2R,4S)-2-hydroxymethyl-4-hydroxy-1-p-toluenesulfonyl)-pyrrolidine in 0.5 lof pyridine was added 250 g (1.32 mol) of p-toluenesulfonyl chloride in1 portions in order to keep the temperature of the reaction below 15° C.for 1 hour and then warmed to room temperature. After 12 hours anadditional 125 g (656 mmol) of p-toluenesulfonyl chloride was added andthe mixture was allowed to stir at room temperature for 16 additionalhours. The mixture was then cooled with an ice bath and 3 l of 10%aqueous hydrogen chloride solution was carefully added. A whiteprecipitate formed which was isolated via filtration and then taken in 1l of ethanol and heated to reflux for 30 minutes. The mixture was thencooled and the solids were filtered and dried under reduced pressure togive 213 g of product in 80% yield. M.P.=134°-135° C.

EXAMPLE 4 (2S,4R)-1-(4-Toluenesulfonyl)-2-(chloromethyl)-4-(4-toluenesulfonyloxy)-pyrrolidine

To an ice-cold solution of 170 g (626.5 mmol) of (2R,4S)-2-hydroxymethyl-4-hydroxy-1-(4-toluenesulfonyl)-pyrrolidine in 0.5 lof pyridine was added 250 g (1.32 mol) of p-toluenesulfonyl chloride inone portion and the reaction was warmed to 50° C. After 6 hours themixture was cooled with an ice bath and 3 l of 10% aqueous hydrogenchloride solution was carefully added. A white precipitate formed whichwas isolated via filtration and then taken in 1 l of ethanol and heatedto reflux for 30 minutes. The mixture was then cooled and the solidswere filtered and dried under reduced pressure to give 195 g of productin 70% yield. M.P.=145°-146° C.

EXAMPLE 5 (1S,4S)-2-(4-Toluenesulfonyl)-5-methyl-2,5-diazabicyclo-[2.2.1]heptane

A Parr bottle was charged with 115 g (198.4 mmol) of (2S,4R)-1-(4-toluenesulfonyl)-2-(p-toluenesulfonyloxymethyl)-4-(4-toluenesulfonyloxy)-pyrrolidineand 690 ml of methanol and the bottle was then tared. Methylamine gaswas bubbled through the methanol solution until 62 g (2 mol) of the gashas dissolved. The bottle was then sealed and heated to 90° C. Afterheating for 16 hours the reaction was cooled and the solvent wasevaporated at reduced pressure. The residual solids were thenpartitioned between 500 ml of methylene chloride and 400 ml of 10%aqueous sodium hydroxide solution. The layers were separated and theorganic layer was washed with 400 additional ml of 10% aqueous sodiumhydroxide solution, and then dried over sodium sulfate. Evaporation ofthe solvent under reduced pressure provided 47.5 g of the desiredproduct which represents a 90% yield. M.P.=87°-88° C.

EXAMPLE 6 (1S,4S)-2-(4-Toluenesulfonyl)-5-methyl-2,5-diazabicyclo-[2.2.1]heptane

A Parr bottle was charged with 3.8 g (8.56 mmol) of (2S,4R)-1-(4-toluenesulfonyl)-2-(chloromethyl)-4-(4-toluenesulfonyloxy)-pyrrolidineand 25 ml of methanol and the bottle was then tared. Methylamine gas wasbubbled through the methanol solution until 2.65 g (85.6 mmol) of thegas had dissolved. The bottle was then sealed and heated to 90° C. Afterheating for 16 hours the reaction was cooled and the solvent wasevaporated at reduced pressure. The residual solids were thenpartitioned between 50 ml of methylene chloride and 40 ml of 10% aqueoussodium hydroxide solution. The layers were separated and the organiclayer was washed with 30 additional ml of 10% aqueous sodium hydroxidesolution, and then dried over sodium sulfate. Evaporation of the solventunder reduced pressure provided 1.73 g of the desired product whichrepresents a 76% yield. M.P.=87°-88° C.

EXAMPLE 7 (1S, 4S)-2-Methyl-2,5-diazabicyclo-[2.2.1]-heptane,dihydrobromide

60 g (225 mmol) of (1S,4S)-2-(4-Toluenesulfonyl)-5-methyl-2,5-diazabicyclo-[2.2.1]heptane wassuspended in 900 ml of 30% hydrogen bromide in acetic acid and themixture was allowed to stir at room temperature. After 6 hours theacetic acid was removed under aspirator pressure to 1/4 of the originalvolume and 1800 ml of ethylacetate was then added. A solid precipitatedand was filtered under an inert atmosphere. The product wasrecrystallized by dissolving in a minimum amount of methanol at reflux.Cooling followed by the addition of 400 ml of isopropyl alcohol provideda white solid which was filtered and dried under reduced pressure. Theproduct weighed 48 g which represents an 81% yield. M.P.=258°-259° C.(coloration occurs at 234° C.). [α]_(D) =+13.21° (c=0.946, CH₃ OH)

EXAMPLE 8 Allo-4-cis-hydroxy-D-proline ethyl ester hydrochloride

80 g of 4-cis-hydroxy-D-proline (0.61 mol) was suspended in 500 ml ofanhydrous ethanol and anhydrous HCl gas was allowed to bubble throughthe mixture until the reaction became homogeneous. The reaction was thenheated to reflux for 5 hours and the volume of the solvent was reducedby one half. 100 ml of diethylether was added and the mixture was keptin a freezer overnight. The resulting precipitate was filtered andwashed with diethylether and dried under reduced pressure to yield 111 gof product (93% yield). M.P. 152°-153° C.

EXAMPLE 9 Allo-1-(4-Toluenesulfonyl)-4-(4-toluenesulfonyloxy)-D-prolineethyl ester

To 110 g (562 mmol) of the allo-4-hydroxy-D-proline ethyl esterhydrochloride was added 1 liter of pyridine and 79 ml of triethylamineat 0° C. After stirring the mixture for 10 minutes, 242.1 g (1.24 mol)of p-toluenesulfonyl chloride was added in small portions to control thetemperature between 0°-5° C. and the reaction was allowed to stir at 0°C. overnight. The next day the reaction was added to 750 ml of ice coldwater and the slurry was left to stir at room temperature for 1 hour.The solids were filtered and dried in a vacuum oven at 30° C. for 48hours to provide 243.9 g of product (92% yield). M.P.=122°-123° C.

EXAMPLE 10 4-(Acetyloxy)-1-(4-toluenesulfonyl)-D-proline ethyl ester

To 218 g (466 mmol) ofallo-1-(4-toluenesulfonyl)-4-(4-toluenesulfonyloxy)-D-proline ethylester in 1500 ml of toluene was added 81 g (606 mmol) of tetramethylammonium acetate and the mixture was heated to reflux for 2 hours. Thereaction was cooled, washed with 2×500 ml of water and dried over sodiumsulfate. Evaporation of the solvent and drying the resulting solids in avacuum oven overnight at 30° C. provided 120.6 g of product (72% yield).M.P.=82°-83° C.

EXAMPLE 11 1-(4-Toluenesulfonyl-4-hydroxy-D-proline

To 127.9 g (359.9 mmol) of 4-(acetyloxy)-1-(4-toluenesulfonyl)-D-prolineethyl ester in 640 ml of THF was added 100 g (1.8 mol) of KOH dissolvedin 640 ml of water at 0° C. The mixture was warmed to room temperatureand allowed to stir for 2 hours. The organic solvents were removed invacuo and the Ph of the resulting mixture was adjusted to neutral withconcentrated HCl. A precipitate formed which was filtered and driedovernight in a vacuum oven at 25° C. to provide 86.2 g of product (84%yield). M.P.=147°-149° C.

EXAMPLE 12 (2R,4S)-2-Hydroxymethyl-4-hydroxy-1-(4-toluene-sulfonyl)-pyrrolidine

To 900 ml of THF was added 21.75 g (574.9 mmol) of sodium borohydrideand the mixture was cooled to 10° C. before 97.92 ml (776.2 mmol) ofborontrifluoride etherate was added dropwise over a period of 1 hour.Then 82 g (287.4 mmol) of N-(4-toluenesulfonyl)-4-hydroxy-D-proline wasadded carefully in 300 ml of THF at 0° C. and the mixture was warmed toroom temperature and allowed to stir for 16 hours. The reaction wascooled to 0° C. and quenched with methanol; 10% aqueous HCl solution wasthen added and the mixture was gently heated to 60° C. for 1 hour. ThepH of the reaction was adjusted to neutral with 50% aqueous sodiumhydroxide solution and the volatiles were evaporated under reducedpressure. The product was then isolated via filtration and the filtercake was washed with water. Drying under vacuum at 60° C. for 12 hoursyielded 78 g of the product as a white solid in 100% yield.M.P.=131°-132° C.

EXAMPLE 13 (2R,4S)-1-(4-Toluenesulfonyl)-2-(4-toluenesulfonyloxymethyl)-4-(4-toluenesulfonyloxy)-pyrrolidine

This compound was prepared from the compound of Example 12 by theprocess described in Example 3. M.P.×125°-130° C.

EXAMPLE 14 (2R,4S)-1-(4-Toluenesulfonyl)-2-chloromethyl-4-(4-toluenesulfonyloxy)-pyrroline

This compound was prepared from the compound of Example 13 by theprocess described in Example 4. M.P.×141°-143° C.

EXAMPLE 15 (1R,4R)-2-(4-Toluenesulfonyl)-5-methyl-2,5-diazabicyclo-[2.2.1]heptane

This compound was prepared from the compound of Example 14 by theprocess described in Examples 5 and 6. M.P.×82°-87° C.

EXAMPLE 16 (1R, 4R)-2-Methyl-2,5-diazabicyclo-[2.2.1]-heptane,dihydrobromide

This compound was prepared from the compound of Example 15 by theprocess described in Example 7. M.P.×260°-262° C. (coloration occurs at240° C.). [α]_(D) =-13.0° (c=0.972, methanol)

EXAMPLE 17 1-(4-Toluenesulfonyl)-4-hydroxy-D-proline

To 10 g (76.30 mmol) of 4-hydroxy-D-proline in 75 ml of water was added17.45 g (91.6 mmol) of 4-toluenesulfonyl chloride and 17 g (160.2 mmol)of sodium carbonate and the mixture was allowed to stir for 24 hours atroom temperature. The reaction was then acidified to pH 1 by the carefuladdition of 10% aqueous HCl solution and the product was isolated byfiltration. After drying at high vaccum, 18.5 g of product was isolated(85% yield). M.P.=145°-146° C.

EXAMPLE 18 (2S, 4S)-2-Hydroxymethyl-4-hydroxy-1-(4-toluenesulfonyl)pyrrolidine

4.14 g (109.5 mmol) of sodium borohydride was suspended in 150 ml of THFat 0° C. and 17.6 ml (142.2 mmol) of borontrifluoride etherate was addeddropwise over a period of 10 minutes. 15.6 g (54.7 mmol) of1-(4-toluenesulfonyl)-4-hydroxy-D-proline was added in portions and themixture was allowed to stir at room temperature for 16 hours. Thereaction was then cooled to 0° C. and quenched with methanol; 10%aqueous HCl solution was then added and the mixture was gently heated to60° C. for 1 hour. The pH of the reaction was adjusted to neutral with50% aqueous sodium hydroxide solution and the volatiles were evaporatedunder reduced pressure. The product was then isolated via filtration andthe filter cake was washed with water. Drying under vacuum at 60° C. for12 hours yielded 10.2 g of the product as a white solid in 69% yield.M.P.=103°-105° C.

EXAMPLE 19 (2R,4S)-2-Chloromethyl-4-chloro-1-(1-toluenesulfonyl)pyrrolidine

To 1 g (3.68 mmol) of (2S,4S)-2-hydroxymethyl-4-hydroxy-1-(4-toluenesulfonyl)pyrrolidine in 6 mlof pyridine was added 1.76 g (9.21 mmol) of p-toluenesulfonyl chlorideand the mixture was allowed to stir at room temperature for 2 hours andthen heated to 95° C. for 2 additional hours. The reaction was thenquenched with 10% aqueous HCl solution and extracted with methylenechloride. Chromatography of the resulting oil on silica gel (25%ethylacetate-75% hexane) provided 0.75 g of product (53% yield).M.P.=103°-105° C.

EXAMPLE 20(1R,4R)-2-(4-Toluenesulfonyl)-5-methyl-2,5-diazabicyclo-[2.2.1]heptane

A Parr bottle was charged with 0.5 g (1.29 mmol) of(2R,4S)-2-chloromethyl-4-chloro-1-(4-toluenesulfonyl)pyrrolidine and 6ml of methanol and the bottle was tared. Methylamine gas was thenbubbled through the methanol solution until 0.4 g (12.9 mol) of the gashad dissolved. The bottle was then sealed and heated to 110° C. Afterheating for 16 hours, the reaction was cooled and the solvent wasevaporated at reduced pressure. The residual solids were partitionedbetween 50 ml of methylene chloride and 40 ml of 10% aqueous NaOHsolution. The layers were separated and the organic layer was washedwith 40 additional milliliters of 10% aqueous NaOH solution, and thendried over Na₂ SO₄. Evaporation of the solvent under reduced pressureprovided 309 mg of the desired product which represents a 90% yield.M.P.=82°-87° C. [α]_(D) =-16.8° (c=1.038, CH₃ OH).

EXAMPLE 21 1-(Carbobenzyloxy)-4-hydroxy-L-proline

To 20 g (152.5 mmol) of 4-hydroxy-L-proline in 35 ml of water was added36.7 g (436.8 mmol) of sodium bicarbonate and the mixture was cooled to10° C. before 32.5 g (190.5 mmol) of benzylchloroformate wa addeddropwise. The cooling bath was then removed and the mixture was allowedto stir for 24 hours at room temperature. The pH of the reaction wasthen adjusted to 1 with concentrated HCl solution and the mixture wasextracted with 3×100 ml portions of methylene chloride. The organiclayers were dried over Na₂ SO₄ and evaporated in vacuum to provide 36.4g of the product as an oil (90% yield). NMR(CDCl₃): 7.30 (m,5H,aromatic), 5.12 (m,2H), 4.50 (m,2H), 4.36 (m,2H), 3.6 (m,2H), 2.38(m,2H).

EXAMPLE 22(2S,4R)-2-Hydroxymethyl-4-hydroxy-1(carbobenzyloxy)pyrrolidine

To 200 ml (0.2 mol) of borane. THF complex was added 27.8 g (0.1 mol) of1-(carbobenzyloxy)-4-hydroxy-L-proline in 50 ml of THF at 0° C. After 16hours of stirring at room temperature, 100 ml of water was addedcarefully followed by 12 ml of 6N aqueous HCl solution and the mixturewas extracted with 3×100 ml of methylene chloride. The combined organicextracts were dried over MgSO₄ and evaporated to yield 22.6 g of theproduct (oil, 90% yield). NMR(CDCl₃): 7.40 (m,5H), 5.10 (m,2H), 4.90(m,1H), 4.65 (m,1H), 4.35 (m,1H), 4.17 (m,1H), 3.60 (m,3H), 2.05 (m,1H),1.70 (m,1H).

EXAMPLE 23(2S,4R)-1-(Carbobenzyloxy)-2-(4-toluenesulfonyloxymethyl)-4-(4-toluenesulfonyloxy)-pyrrolidine

To an ice-cold solution of 150 g (596.9 mmol) of(2R,4S)-2-hydroxymethyl-4-hydroxy-N-(carbobenzyloxy)-pyrrolidine in 0.5l of pyridine was added 250 g (1.32 mol) of 4-toluenesulfonyl chloridein 3 portions to keep the temperature of the reaction below 15° C. for 1hour and then warmed to room temperature. After 12 hours, an additional125 g (656 mmol) of p-toluenesulfonyl chloride was added and the mixturewas allowed to stir at room temperature for 16 additional hours. Themixture was then cooled with an ice bath and 3 l of 10% aqueous HClsolution was carefully added. The mixture was extracted with 2×250 ml ofmethylene chloride and dried over MgSO₄. Evaporation of the solventprovided 274 g of the product as an oil (82% yield). NMR(CDCl₃): 7.70 &7.40 (m,9H, aromatic), 5.0 (m,3H), 4.43 (dd,1H), 4.12 (m,1H), 4.02(m,H), 3.70 (m,1H), 3.88 (m,1H), 2.42 (m,6H), 2.15 (m,2H).

EXAMPLE 24(1S,4S)-2-(Carbobenzyloxy)-5-methyl-2,5-diazabicyclo[2.2.1]heptane

A Parr bottle was charged with 22 g (40.2 mmol) of(2S,4R)-1-(carbobenzyloxy)-2-(p-toluenesulfonyloxymethyl)-4-(4-toluenesulfonyloxy)-pyrrolidineand 100 ml of methanol and the bottle was then tared. Methylamine gaswas bubbled through the methanol solution until 12.4 g (402 mmol) of thegas had dissolved. The bottle was then sealed and heated to 80° C. Afterheating for 16 hours, the reaction was cooled and the solvent wasevaporated at reduced pressure. The residual solids were thenpartitioned between 200 ml of methylene chloride and 150 ml of 10%aqueous NaOH solution. The layers were separated and the organic layerwas washed with 100 additional ml of 10% aqueous NaOH solution, and thendried over Na₂ SO₄. Evaporation of the solvent under reduced pressureprovided 9.0 g of the desired product (oil) which represents a 91%yield. NMR(CDCl₃): 7.32 (aromatic, 5H), 5.1 (d,2H), 4.4 (d,1H), 3.58(dd, 1H), 3.4 (d,1H), 3.22 (m,1H), 2.88 (m,1H), 2.7 (d,1H), 2.52 (d,1H),2.40 (s,3H), 1.86 (d,1H), 1.7 (m,1 H).

EXAMPLE 25 (1S,4S)-2-Methyl-2,5-diazabicyclo-[2.2.1]heptane

3.0 g (12.19 mmol) of(1S,4S)-2-(carbobenzyloxy)-5-methyl-2,5-diazabicyclo-[2.2.1]heptane wasdissolved in 30 ml of methanol, 600 mg (0.2% by weight) of 10% Pd oncarbon was added and the mixture was hydrogenated at 50 p.s.i. for 16hours. The mixture was filtered and the solvent was evaporated andreplaced by 30 ml of methylene chloride. This mixture was then driedover K₂ CO₃ and evaporated to yield 1.25 g of the diamine product in 92%yield. NMR(CDCl₃): 4.5 (broad,1H), 3.43 (broad,1H), 3.12 (broad,1H),3.05 (d,1H), 2.68 (m,2H), 2.32 (d,1H), 2.21 (s,3H), 1.65 (d,1H), 1.44(d,1H). CMR(CDCl₃): 62.33, 57.30, 47.18, 40.70, 35.98, 35.35.

We claim:
 1. A process for preparing a compound of the formula ##STR13##or the enantiomer, racemate, or acid addition salt thereof, wherein Y ishydrogen or XR₂, R₁ is hydrogen or C₁ -C₆ alkyl, and X and R₂ are asdefined below, which comprises(a) reacting a compound of the formula##STR14## or the enantiomer or the racemate thereof, wherein X is SO₂ orCO₂, R₂ and R₃ are each independently C₁ -C₆ alkyl, trifluoromethyl,benzyl, or phenyl optionally substituted by one or two C₁ -C₆ alkyl,halogen, nitro, methoxy or trifluoromethyl, and R₄ is halogen or OSO₂ R₃wherein R₃ is as defined above, with a (C₁ -C₆)alkylamine or ammonia toform a compound of the formula IA wherein Y is XR₂, and X, R₁ and R₂ areas defined above, and, if desired, (b) reducing or hydrolyzing thecompound of formula IA wherein Y is XR₂ to form a compound of formula IAwherein Y is hydrogen.
 2. A process according to claim 1 wherein said C₁-C₆ alkylamine is methylamine, X is SO₂, and R₂ is p-tolyl.
 3. Acompound of the formula ##STR15## or the enantiomer or racemate thereof,wherein X is SO₂ or CO₂, R₂ is C₁ -C₆ alkyl, trifluoromethyl, benzyl, orphenyl optionally substituted by one or two C₁ -C₆ alkyl, halogen,nitro, methoxy or trifluoromethyl, and R₅ is C₁ -C₆ alkyl.
 4. A compoundaccording to claim 3 wherein X is SO₂ and R₂ is paratolyl.
 5. A compoundaccording to claim 3 wherein X is SO₂, R₂ is paratolyl, and R₅ ismethyl.
 6. A process according to claim 1 wherein said compound offormula III is prepared by reacting a compound of the formula ##STR16##or the enantiomer or racemate thereof, wherein X is SO₂ or CO₂, and R₂is C₁ -C₆ alkyl, trifluoromethyl, benzyl, or phenyl optionallysubstituted by C₁ -C₆ alkyl, halogen, nitro, methoxy, ortrifluoromethyl, with a compound of the formula

    R.sub.3 SO.sub.2 X.sup.1                                   V

wherein R₃ is C₁ -C₆ alkyl, trifluoromethyl, or phenyl optionallysubstituted by C₁ -C₆ alkyl, halogen, nitro, methoxy or trifluoromethyl,and X¹ is halogen or OSO₂ R₃, wherein R₃ is as defined above.
 7. Aprocess according to claim 6 wherein X is SO₂ and R₂ is paratolyl.
 8. Aprocess according to claim 6 wherein said compound of formula IV isprepared by reducing a compound of the formula ##STR17## or theenantiomer or racemate thereof, wherein X is SO₂ or CO₂, and R₂ is C₁-C₆ alkyl, trifluoromethyl, benzyl, or phenyl optionally substituted byone or two C₁ -C₆ alkyl, halogen, nitro, methoxy or trifluoromethyl. 9.A process according to claim 8 wherein said reduction is carried outwith sodium borohydride in the presence of borontrifluoride etherate.10. A process according to claim 8 wherein X is SO₂ and R₂ is paratolyl.11. A process according to claim 8 wherein said compound of formula VIis prepared by reacting 4-hydroxy-L-proline with a compound of theformula

    R.sub.2 X X.sup.1                                          VII

wherein X is SO₂ or CO₂, R₂ is C₁ -C₆ alkyl, trifluoromethyl, benzyl, orphenyl optionally substituted by one or two C₁ -C₆ alkyl, halogen,nitro, methoxy or trifluoromethyl, and X¹ is halogen, an azide or OSO₂R₂, wherein R₂ is as defined above, in the presence of alkali metalcarbonate.
 12. A process according to claim 11 wherein X is SO₂ and R₂is paratolyl. s c